Menopause, a natural phenomenon for middle-aged women, is characterized by a cessation of ovarian activity, disrupted sleep patterns, night sweating, osteoporosis and enhanced cardiovascular malfunction. To identify suitable models for studying the causes of this health-relevant syndrome, we are monitoring several brain, pituitary and ovarian events in aged female macaques, in reproductively competent rhesus macaques before and after local ovarian x-irradiation, and in females with neurally-induced norepinephrine (NE) dysfunction. Aged female macaques displayed anovulation, low ovarian steroid secretion (both estradiol-17 [E] and progesterone [P]), and modest elevations in bioactive plasma luteinizing hormone (LH) levels. These bioactive LH levels were increased to those in castrate monkeys, i.e., 150-300 ng/ml, by continuous infusions of 1 fg gonadotropin-releasing hormone (GnRH) for 6 min every hour for 2-3 months, thereby suggesting that pituitary gonadotropes were functional. Despite this enhanced LH secretion, the ovaries remained inactive, i.e., no change in E and P and thus presumed failure of either follicular or luteal development. Preliminary data in ovarian x-irradiated macaques indicate this treatment destroys follicular activity in that low plasma E and P levels occurred soon after irradiation and these low values persisted. Plasma levels of LH in these females were elevated to castrate values without exogenous GnRH infusions. These observations may imply differences in the responsiveness of the brain-pituitary axis of these younger ovarian irradiated females compared with that of the aged menopausal monkeys. In females with brain-blocked NE transporter protein, both endogenous NE and GnRH secretion were sharply enhanced. Also E-administration, at dosages equivalent to those in ovarian-intact preovulatory females, caused endogenous increases in NE secretion at times similar to those when E increases endogenous GnRH release. We hypothesize that ovarian E secretion causes increased neuronal NE activity which prompts hypothalamic GnRH secretion. Lesions of this neurochemical pathway may be a cause of disrupted sleep and "hot flushes" (sweating) that is associated with menopause. Thus we plan to monitor NE and GnRH secretion in the aged and ovarian-irradiated macaque females. Ultimately, these varied group comparisons will provide insight into potential monkey models to study the menopausal syndrome in women.